(R)-malic acid [D-(+)-malic acid] is an unnatural malic acid and is useful as a precursor for the synthesis of various chiral compounds such as an optically active isoserine, an optically active pantolactone, an optically active .beta.-lactam intermediates and an optically active pheromones.
Although L-(-)-malic aid occurs naturally and now being produced from fumaric acid by enzymic method, no efficient process for (R)-malic acid production was developed until now. Chemical hydration of fumaric acid or maleic acid anhydride produce DL-malic acid (racemic malic acid). Several syntheses of (R)-malic acid or its derivatives have been known. Wynberg, Staring et al. [Wynberg, H., Staring, E. G. J., J. Amer. Chem. Soc., Vol. 104, pp. 166 to 168 (1982)] synthesized (R)-malic acid in 79% overall yield by application of asymmetric cycloaddition catalyzed by quinidine. Henrot et al. [Henrot, S., Larcheveque, M., Petit, Y., J. Chem. Soc., Perkin Trans. 1. Synth. Commun., Vol. 16, p. 183 (1986)]described the synthesis of (R)-malic acid from (R)-aspartic acid in three steps and 68% overall yield. Seebach et al. [Hungerbuhler, E., Seebach, D., Wasmuth, D., Helv. Chim. Acta., Vol. 64, p. 1467 (1981)] and also Alpegiani et al. [Alpegiani, M. and Hanessian, S., J. Org. Chem., Vol. 52, pp. 278 to 279 (1987)] described the synthesis of (R)-dimethyl malate from (R,R)-dimethyl tartarate.
(R)-malic acid was also prepared by resolution of DL-malic acid as described in German Patent Application (OLS) No. 2,933,895, JP-A-57-56439, JP-A-60-204741 (the term "JP-A" as used herein refers to a "published unexamined Japanese patent application"), EP-A-149,885 (the term "EP-A" as used herein refers to a "published unexamined European patent application"), Synthesis, p. 214 (1985), and U.S. Pat. No. 4,912,042. High performance liquid chromatography resolved DL-malic acid [Benecke, I , J. Chromatogr., Vol. 291, p. 155 (1984)]. Rom 67,279 (1979) [Chem. Abstr., Vol. 93, 238846a (1980)] described asymmetric synthesis using polarized electrets.
However, these methods are disadvantageous from an industrial viewpoint since the starting materials or resolving agents are expensive. The formation of (S)-malic acid by enzymic method is known as described in Kitahara, K., Fukui, S. and Misawa, M., J. Gen. Appl. Microbiol., Vol. 6, p. 108 (1960). (S)-malic acid was also produced from maleic acid via fumaric acid by a bacterium which has cis-trans-isomerase catalyzing the formation of fumaric acid from maleate [Otsuka, K., Agric. Biol. Chem., Vol. 25, p. 726 (1961)]. Sacks, W. and Jensen, C. O. [Sacks, W., Jensen, C. O., J. Biol. Chem., Vol. 192, p. 231 (1951)] obtained malic acid from maleic acid using a hydratase from corn kernels but enantiomorph of the malic acid formed was not specified. D-malate formation from maleic acid was noted with the extract of mammalian kidney [Taggart, J. V., Angielski, S., Morell, H., Biochem. Biophys. Acta., Vol. 185, p. 220 (1969)]. (R)-malic acid formation from maleic acid using cell-extract of a Pseudomonas strain isolated from soil is described in Rahatekar, H. L., Maskatl, F. S., Subramanian, S. S., Raghavendra Rao, M. R., Indian J. Biochem., Vol. 5, p. 143 (1968) and Hopper, D. J., Chapman, P. J., Sagney, S., Biochem. J., Vol. 110, p. 798 (1968). However, the properties of the enzyme has never been specified and no industrial method enabling the supply of (R)-malic acid has never been developed.